CD6 is a cell surface glycoprotein that is primarily expressed on T cells. Previous in vitro studies have indicated that CD6 is critical in regulating T cell responses and that it could be a target for treating autoimmune diseases. However, research in this field has languished, partially due to the lack of CD6 gene engineered animals to confirm the in vitro results and to explore the potential of biologic therapy in vivo. Recent genome scanning studies from several groups have unanimously identified CD6 as a risk gene for multiple sclerosis (MS), which raises the possibility of using CD6 as a target to develop new therapies for MS. We have studied CD6 knockout (KO) mice and discovered that they are protected from central nervous system injury in experimental autoimmune encephalomyelitis (EAE), an animal model of human MS, further supporting the hypothesis that targeting CD6 could be effective in treating MS. To test this hypothesis, we treated wild type (WT) mice after onset of EAE with a rat anti-mouse CD6 mAb and found that this halted disease progression, but the efficacy of treatment rapidly decreased due to the development of anti-rat IgG antibodies in the treated mice. To address this issue and to be able to test human CD6-targeted reagents in vivo, we have developed CD6 humanized mice that express human CD6 instead of mouse CD6 on their T cells. In pilot treatment studies using these CD6 humanized mice, we found that administration of a mouse anti-human CD6 mAb (UMCD6) at either an early stage (clinical score H1) or late stage (clinical score H2.5) of EAE significantly reversed disease progression and this effect was long-lasting. In this application, using the CD6 humanized mice, we will further test this mAb and another well-characterized mouse anti-human CD6 mAb and a soluble human CD6-Fc chimeric protein to determine their relative effectiveness in treating both chronic progressive EAE, and remitting-relapsing EAE. This study should validate CD6 as a new target for MS therapy and set the stage for further development of the anti-CD6 mAbs and soluble CD6-Fc protein as novel therapeutic agents for MS patients.